The goal of this T32 program is to train new independent investigators who will utilize contemporary genetic and molecular genetic techniques to investigate the underlying mechanisms of aging. The rationale for the focus of our program can be succinctly summarized as follows: 1) The genetic approach to the analysis of the biology and pathobiology of aging has special merit that, by definition, it deals with primary, constitutional, heritable, controls of gene action and thus can inform us as to fundamental mechanisms. 2) The tools for the molecular genetic approach to the pathobiology of aging are becoming increasingly rich and diverse. We thus believe that this focus for gerontological research will be applied with increasing frequency and success. While this may seem obvious given today's prominence of molecular genetics, the field of gerontology does not have so rich a historical background in use of genetic approaches. Thus we believe there is a need for more investigators who are trained in the principles and methods of genetic analysis and in gerontology. Such training is the primary goal of this program. The program currently supports 8 pre- and 8 post-doctoral trainees, and we are requesting an increase to 9 of each category. We provide continuity of training by typically providing support for 3-4 (pre-doc) or 2-3 (post-doc) years. Predoctoral candidates ordinarily begin in their 2nd year of graduate training and post-docs in their 1st year of post-graduate training. The relevance of this program to public health is rooted in fact that age is the primary risk factor for disease in our population: diseases associated with aging are the chief health burden to our society and the primary cause of reduced quality of life. An increased understanding of the genetic mechanisms responsible for the processes that contribute to the burden of disease in aging can have a great positive impact on our society. We are training bright, new scientists who are highly motivated to work to increase this understanding. This competitive renewal application for a training grant requests funds for 9 predoctoral and 9 postdoctoral trainees. The goal is to provide opportunities for research training on molecular genetics approaches to biology and pathology of aging, with special emphasis upon a variety of model organisms and cell cultures that are amenable to genetic analysis (S. cerevisiae, C. elegans, M. domesticus, 14. sapiens); such materials should permit trainees to address fundamental mechanisms highly relevant to aging and age-related diseases, including Alzheimer's disease (AD) and cancer. Didactic experiences will include courses in biochemistry., genetics, cell biology and pathology, research seminars, journal clubs, reviews of on-going research (approximately 60 individual and 6 program-projects, LEAD or center grants in aging), and a course on Molecular Genetic Approaches to Aging, and bi-monthly Aging Journal Club. In addition, trainees will typically participate in weekly lab meetings and in individual conferences with their mentors. Research projects will include efforts to identify genes related to various forms of familial and sporadic AD, delineations of mechanisms of [3 -amyloidogenesis and of its suppression, the role of the Werner Syndrome helicase gene in aging and cancer, studies of free radical injury and defense in relation to aging, DNA damage and mutation in aging, and mechanisms underlying the limited replicative potential of somatic cells.